3-epi-18ß-glycyrrhetinic acid or its glucuronide, the metabolites of glycyrrhizinic acid with individual differences, correlated with diagnostic maker for licorice-induced pseudoaldosteronism in humans.

Licorice is a crude drug that is used in traditional Japanese Kampo medicine and is also used as a sweetener. Occasionally, it causes pseudoaldosteronism (PsA) as a side effect. The major symptoms include hypokalemia, hypertension, edema, and low plasma aldosterone levels. PsA might be caused by the metabolites of glycyrrhizinic acid (GL), a component of licorice. The development of PsA markedly varies among individuals; however, the factors that cause these individual differences remain unknown. In this study, 78 patients who consumed Kampo medicines containing licorice were enrolled, and their laboratory data, including serum potassium levels, plasma aldosterone concentrations (PAC), and the concentrations of GL metabolites in the residual blood and/or urine samples were evaluated. Of the 78 participants, 18ß-glycyrrhetinic acid (GA), 3-epi-GA, 3-oxo-GA, 18ß-glycyrrhetinyl-30-O-glucuronide (GA30G), and 3-epi-GA30G were detected in the serum samples of 65, 47, 63, 62, and 3 participants, respectively. Of the 29 urine samples collected, GA30G and 3-epi-GA30G were detected in 27 and 19 samples. 3-epi-GA30G is a newly found GL metabolite. Moreover, 3-epi-GA, 3-oxo-GA, and 3-epi-GA30G were identified in human samples for the first time. High individual differences were found in the appearances of 3-epi-GA in serum and 3-epi-GA30G in urine, and the concentrations of these metabolites were correlated with serum PsA markers. The inhibitory titers of 3-epi-GA, 3-oxo-GA, GA30G, and 3-epi-GA30G on human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) were almost similar. These findings suggest that 3-epi-GA and/or 3-epi-GA30G are associated with individual differences in the development of PsA. Significance Statement In this study, we detected 3-epi-GA in human serum for the first time. We also identified 3-epi-GA30G as a novel GL metabolite in human urine. These GL metabolite levels showed correlations with markers of PsA. Additionally, there are individual differences in whether or not they appear in the serum/urine. In conclusion, 3-epi-GA/3-epi-GA30G correlates with individual differences in the development of PsA.

Interactions of Body Weight Loss with Lipophilic Toxin Storage: Commentary.

A high incidence of obesity and surplus body fat has been observed in wealthy countries for many decades. It is generally recognized that these excesses contribute to serious disease states, including type 2 diabetes and cardiovascular diseases. On the other hand, the adipose tissue stores relatively safely many environmental lipophilic toxins. However, rapid weight loss mobilizes these toxins to the blood to be exposed to vital organs, such as the brain, lungs, and others. With the introduction of potent diabetic drugs causing rapid weight reduction, the question of mobilization of lipophilic toxins to the blood should be considered. In this commentary, we raised this mobilization of adipose tissue toxins to the readers. Also, we discussed how these toxins may be eliminated from the body through the use of nondigestible fat, such as olestra or lipase inhibitors, such as Xenical.

A Continuous Intestinal Absorption Model to Predict Drug Enterohepatic Recirculation in Healthy Humans: Nalbuphine as a Model Substrate.

Nalbuphine (NAL) is a κ-agonist/µ-antagonist opioid being developed as an oral extended formulation (ER) for the treatment of chronic cough in idiopathic pulmonary fibrosis and itch in prurigo nodularis. NAL is extensively glucuronidated and likely undergoes enterohepatic recirculation (EHR). The purpose of this work is to develop pharmacokinetic models for NAL absorption and enterohepatic recirculation (EHR). Clinical pharmacokinetic (PK) data sets in healthy subjects from three trials that included IV, oral solution, and ER tablets in fed and fasted state and two published trials were used to parametrize a novel partial differential equation (PDE)-based model, termed "PDE-EHR" model. Experimental inputs included in vitro dissolution and permeability data. The model incorporates a continuous intestinal absorption framework, explicit liver and gall bladder compartments, and compartments for systemic drug disposition. The model was fully PDE-based with well-stirred compartments achieved by rapid diffusion. The PDE-EHR model accurately reproduces NAL concentration-time profiles for all clinical data sets. NAL disposition simulations required inclusion of both parent and glucuronide recirculation. Inclusion of intestinal P-glycoprotein efflux in the simulations suggests that NAL is not expected to be a victim or perpetrator of P-glycoprotein-mediated drug interactions. The PDE-EHR model is a novel tool to predict EHR and food/formulation effects on drug PK. The results strongly suggest that even intravenous dosing studies be conducted in fasted subjects when EHR is suspected. The modeling effort is expected to aid in improved prediction of dosing regimens and drug disposition in patient populations.

Emerging drugs for the treatment of progressive familial intrahepatic cholestasis: a focus on phase II and III trials.

INTRODUCTION: Progressive familial intrahepatic cholestasis (PFIC) is a group of disorders characterized by inappropriate bile formation, causing hepatic accumulation of bile acids and, subsequently, liver injury. Until recently, no approved treatments were available for these patients. AREAS COVERED: Recent clinical trials for PFIC treatment have focused on intestine-restricted ileal bile acid transporter (IBAT) inhibitors. These compounds aim to reduce the pool size of bile acids by interrupting their enterohepatic circulation. Other emerging treatments in the pipeline include systemic IBAT inhibitors, synthetic bile acid derivatives, compounds targeting bile acid synthesis via the FXR/FGF axis, and chaperones/potentiators that aim to enhance the residual activity of the mutated transporters. EXPERT OPINION: Substantial progress has been made in drug development for PFIC patients during the last couple of years. Although data concerning long-term efficacy are as yet only scarcely available, new therapies have demonstrated robust efficacy in a considerable fraction of patients at least on the shorter term. However, a substantial fraction of PFIC patients do not respond to these novel therapies and thus still requires surgical treatment, including liver transplantation before adulthood. Hence, there is still an unmet medical need for long-term effective medical, preferably non-surgical, treatment for all PFIC patients.

Normally, the liver produces bile which is a route of secretion of waste products from the body and also helps in the intestinal absorption of fats from the diet. The bile goes from the liver, through the bile duct to the intestines and components are taken up again at the end of the intestine and transported back to the liver. However, progressive familial intrahepatic cholestasis (PFIC in short) is a group of diseases where bile stays in the liver and damages it. PFIC often causes symptoms already in very young children, like itch and jaundice (getting a slight yellow color). Patients get more and worse symptoms over time and may eventually need a liver transplantation. This review discusses what drugs have been developed for PFIC recently and what drugs are in development now. Two new drugs for PFIC have been developed and approved in the last few years: odevixibat and maralixibat. These drugs help bile in the intestines leave the body via the stool and prevent bile from going back to the liver instead. Drugs in development aim to either 1) do the same, 2) make the bile less toxic, 3) reduce the production of bile, or 4) help bile go from the liver into the bile ducts. There has been a lot of progress in drug development for PFIC in the last few years. The new drugs have helped a considerable number of patients, but many patients still do not respond to these new drugs, keep having symptoms and may need surgery. Therefore, despite considerable progress, research needs to continue for an effective treatment for all PFIC patients.

Roles for Bile Acid Signaling and Nonsense-Mediated Ribonucleic Acid Decay in Small Bowel Resection-Associated Liver Injury.

INTRODUCTION: Massive intestinal loss resulting in short bowel syndrome has been linked to intestinal failure associated liver disease. Efforts to elucidate the driving force behind the observed hepatic injury have identified inflammatory mediators, alterations in the microbiome, extent of structural and functional intestinal adaptation, and toxic shifts in the bile acid pool. In the present study, we posit that ileocecal resection interrupts the delivery of these hepatotoxic substances to the liver by physically disrupting the enterohepatic circulation, thereby shielding the liver from exposure to the aforementioned noxious stimuli. METHODS: Mice underwent sham, 50% proximal, or 50% distal small bowel resection (SBR), with or without tauroursodeoxycolic acid supplementation. Enterohepatic signaling and nonsense-mediated ribonucleic acid (RNA) decay were evaluated and correlated with hepatic injury. RESULTS: When compared to 50% proximal SBR, mice that underwent ileocecal resection exhibited reduced hepatic oxidative stress and exhibited a more physiological bile acid profile with increased de novo bile acid synthesis, enhanced colonic bile acid signaling, and reduced hepatic proliferation. Distal intestinal resection promoted an adaptive response including via the nonsense-mediated RNA decay pathway to satisfactorily process injurious messenger RNA and successfully maintain homeostasis. By contrast, this adaptive response was not observed in the proximal SBR group and hepatic injury persisted. CONCLUSIONS: In summary, interruption of enterohepatic circulation via ileocecal resection abrogates the liver's exposure to toxic and inflammatory mediators while promoting physiological adaptations in bile acid metabolism and maintaining existing homeostatic pathways.

Importance of Considering Fed-State Gastrointestinal Physiology in Predicting the Reabsorption of Enterohepatic Circulation of Drugs.

PURPOSE: The purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles. METHODS: Meloxicam and ezetimibe were used as model drugs. The extent of the entrapment of drugs inside bile micelles was evaluated using the solubility ratio of Fed State Simulated Intestinal Fluid version 2 (FeSSIF-V2) to Fasted State Simulated Intestinal Fluid version 2 (FaSSIF-V2). Prediction accuracy was evaluated using the Mean Absolute Percentage Error (MAPE) value, calculated from the observed and predicted oral PK profiles. RESULTS: The solubilization of ezetimibe by bile micelles was clearly observed while that of meloxicam was not. Assuming that only drugs in the free fraction of micelles permeate through the intestinal membrane, PK simulation for ezetimibe was performed in both scenarios with and without compensation by the permeation rate constant. The MAPE value of Zetia® tablet, containing ezetimibe, was lower with compensation than without compensation. By contrast, Mobic® tablet, containing meloxicam, showed a relatively low MAPE value even without compensation. CONCLUSION: For drugs which undergo EHC and can be solubilized by bile micelles, compensating for the permeation rate constant in the reabsorption process based on the free fraction ratio appears an important factor in increasing the accuracy of PK profile prediction.

Assessment of Fetal Exposure and Elimination of Perfluoroalkyl and Polyfluoroalkyl Substances: New Evidence from Paired Serum, Placenta, and Meconium Samples.

Multiple pieces of evidence have shown that prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) is closely related to adverse birth outcomes for infants. However, difficult access to human samples limits our understanding of PFASs transport and metabolism across the human placental barrier, as well as the accurate assessment of fetal PFASs exposure. Herein, we assess fetal exposure to 28 PFASs based on paired serum, placenta, and meconium samples. Overall, 21 PFASs were identified first to be exposed to the fetus prenatally and to be metabolized and excreted by the fetus. In meconium samples, 25 PFASs were detected, with perfluorooctane sulfonate and perfluorohexane sulfonic acid being the dominant congeners, suggesting the metabolism and excretion of PFASs through meconium. Perfluoroalkyl sulfonic acids might be more easily eliminated through the meconium than perfluorinated carboxylic acids. Importantly, based on molecular docking, MRP1, OATP2B1, ASCT1, and P-gp were identified as crucial transporters in the dynamic placental transfer of PFASs between the mother and the fetus. ATSC5p and PubchemFP679 were recognized as critical structural features that affect the metabolism and secretion of PFASs through meconium. With increasing carbon chain length, both the transplacental transfer efficiency and meconium excretion efficiency of PFASs showed a structure-dependent manner. This study reports, for the first time, that meconium, which is a noninvasive and stable biological matrix, can be strong evidence of prenatal PFASs exposure.

Hepatic injury and ileitis associated with gut microbiota dysbiosis in mice upon F-53B exposure.

Chlorinated polyfluorinated ether sulfonate (F-53B), a substitute of perfluorooctane sulfonic acid (PFOS), has attracted significant attention for its link to hepatotoxicity and enterotoxicity. Nevertheless, the underlying mechanisms of F-53B-induced enterohepatic toxicity remain incompletely understood. This study aimed to explore the role of F-53B exposure on enterohepatic injury based on the gut microbiota, pathological and molecular analysis in mice. Here, we exposed C57BL/6 mice to F-53B (0, 4, 40, and 400 µg/L) for 28 days. Our findings revealed a significant accumulation of F-53B in the liver, followed by small intestines, and feces. In addition, F-53B induced pathological collagen fiber deposition and lipoid degeneration, up-regulated the expression of fatty acid ß-oxidation-related genes (PPARα and PPARγ, etc), while simultaneously down-regulating pro-inflammatory genes (Nlrp3, IL-1ß, and Mcp1) in the liver. Meanwhile, F-53B induced ileal mucosal barrier damage, and an up-regulation of pro-inflammatory genes and mucosal barrier-related genes (Muc1, Muc2, Claudin1, Occludin, Mct1, and ZO-1) in the ileum. Importantly, F-53B distinctly altered gut microbiota compositions by increasing the abundance of Akkermansia and decreasing the abundance of Prevotellaceae_NK3B31_group in the feces. F-53B-altered microbiota compositions were significantly associated with genes related to fatty acid ß-oxidation, inflammation, and mucosal barrier. In summary, our results demonstrate that F-53B is capable of inducing hepatic injury, ileitis, and gut microbiota dysbiosis in mice, and the gut microbiota dysbiosis may play an important role in the F-53B-induced enterohepatic toxicity.

Colchicine disrupts bile acid metabolic homeostasis by affecting the enterohepatic circulation in mice.

Although the medicinal properties of colchicine (COL) have been widely known for centuries, its toxicity has been the subject of controversy. The narrow therapeutic window causes COL to induce gastrointestinal adverse effects even when taken at recommended doses, mainly manifested as nausea, vomiting, and diarrhea. However, the mechanism of COL-induced gastrointestinal toxic reactions remains obscure. In the present study, the mice were dosed with COL (2.5 mg/kg b.w./day) for a week to explore the effect of COL on bile acid metabolism and the mechanism of COL-induced diarrhea. The results showed that COL treatment affected liver biochemistry in mice, resulting in a significant down-regulation of the mRNA expression levels of bile acid biosynthesis regulators Cyp7a1, Cyp8b1, Cyp7b1, and Cyp27a1 in liver tissues. The mRNA expression levels of bile acid transporters Ntcp, Oatp1, Mrp2, Ibabp, Mrp3, Osta, and Ostb in liver and ileum tissues were also significantly down-regulated. In addition, COL treatment significantly inhibited the mRNA expression levels of Fxr and its downstream target genes Shp, Lrh1, and Fgf15 in liver and ileum tissues, affecting the feedback regulation of bile acid biosynthesis. More importantly, the inhibition of COL on bile acid transporters in ileal and hepatic tissues affected bile acid recycling in the ileum as well as their reuptake in the liver, leading to a significantly increased accumulation of bile acids in the colon, which may be an important cause of diarrhea. In conclusion, our study revealed that COL treatment affected bile acid biosynthesis and enterohepatic circulation, thereby disrupting bile acid metabolic homeostasis in mice.

Helicobacters and cancer, not only gastric cancer?

The Helicobacter genus actually comprises 46 validly published species divided into two main clades: gastric and enterohepatic Helicobacters. These bacteria colonize alternative sites of the digestive system in animals and humans, and contribute to inflammation and cancers. In humans, Helicobacter infection is mainly related to H. pylori, a gastric pathogen infecting more than half of the world's population, leading to chronic inflammation of the gastric mucosa that can evolve into two types of gastric cancers: gastric adenocarcinomas and gastric MALT lymphoma. In addition, H. pylori but also non-H. pylori Helicobacter infection has been associated with many extra-gastric malignancies. This review focuses on H. pylori and its role in gastric cancers and extra-gastric diseases, as well as malignancies induced by non-H. pylori Helicobacters. Their different virulence factors and their involvement in carcinogenesis is discussed. This review highlights the importance of both gastric and enterohepatic Helicobacters in gastrointestinal and liver cancers.

The Hylemon-Björkhem pathway of bile acid 7-dehydroxylation: history, biochemistry, and microbiology.

Bile acids are detergents derived from cholesterol that function to solubilize dietary lipids, remove cholesterol from the body, and act as nutrient signaling molecules in numerous tissues with functions in the liver and gut being the best understood. Studies in the early 20th century established the structures of bile acids, and by mid-century, the application of gnotobiology to bile acids allowed differentiation of host-derived "primary" bile acids from "secondary" bile acids generated by host-associated microbiota. In 1960, radiolabeling studies in rodent models led to determination of the stereochemistry of the bile acid 7-dehydration reaction. A two-step mechanism was proposed, which we have termed the Samuelsson-Bergström model, to explain the formation of deoxycholic acid. Subsequent studies with humans, rodents, and cell extracts of Clostridium scindens VPI 12708 led to the realization that bile acid 7-dehydroxylation is a result of a multi-step, bifurcating pathway that we have named the Hylemon-Björkhem pathway. Due to the importance of hydrophobic secondary bile acids and the increasing measurement of microbial bai genes encoding the enzymes that produce them in stool metagenome studies, it is important to understand their origin.

Biological tuners to reshape the bile acid pool for therapeutic purposes in non-alcoholic fatty liver disease.

Bile acids synthesized within the hepatocytes are transformed by gut microorganisms and reabsorbed into the portal circulation. During their enterohepatic cycling, bile acids act as signaling molecules by interacting with receptors to regulate pathways involved in many physiological processes. The bile acid pool, composed of a variety of bile acid species, has been shown to be altered in diseases, hence contributing to disease pathogenesis. Thus, understanding the changes in bile acid pool size and composition in pathological processes will help to elaborate effective pharmacological treatments. Five crucial steps along the enterohepatic cycle shape the bile acid pool size and composition, offering five possible targets for therapeutic intervention. In this review, we provide an insight on the strategies to modulate the bile acid pool, and then we discuss the potential benefits in non-alcoholic fatty liver disease.

Helicobacter kumamotonensis sp. nov., isolated from human clinical specimens.

A Gram-stain-negative, spiral bacterium (PAGU 1991T) was isolated from the blood of a patient with diffuse large B-cell lymphoma. Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolate was very closely related to Helicobacter equorum LMG 23362T (99.1 % similarity), originally isolated from a faecal sample from a healthy horse. PAGU 1991T was also very closely related to PAGU 1750 in our strain library (=CCUG 41437) with 99.7 % similarity. Additional phylogenetic analyses based on the 23S rRNA gene sequence and GyrA amino acid sequence further supported the close relationship between the two human isolates (PAGU 1991T and PAGU 1750) and the horse strain. However, a phylogenetic analysis based on 16S rRNA showed that the two human isolates formed a lineage that was distinct from the horse strain (less than 99.2 % similarity). In silico whole-genome comparisons based on digital DNA-DNA hybridization, average nucleotide identity based on blast and orthologous average nucleotide identity using usearch between the two human isolates and the type strain of H. equorum showed values of less than 52.40, 93.47, and 93.50 %, respectively, whereas those between the two human isolates were 75.8, 97.2, and 97.2 %, respectively. These data clearly demonstrated that the two human isolates formed a single species, distinct from H. equorum. Morphologically, the human isolates could be distinguished by the type of flagella; the human isolates showed a bipolar sheathed flagellum, whereas that of H. equorum was monopolar. Biochemically, the human isolate was characterized by growth at 42 °C under microaerobic conditions and nitrate reduction unability. We conclude that the two human isolates, obtained from geographically and temporally distinct sources, were a novel species, for which we propose the name Helicobacter kumamotonensis sp. nov., with the type strain PAGU 1991T (=GTC 16810T=CCUG 75774T).

Lactiplantibacillus plantarum P101 alleviated lead-induced more severe hepatic injury in obese mice, by promoting fecal lead excretion and enhancing antioxidative defense system.

AIMS: Lead (Pb) is a toxic heavy metal that has been intensively studied, but its toxicity in sub-healthy people remains unclear. This study aims to investigate the adverse effects of Pb in the obese population and validate the feasibility of a potential probiotic strain for the treatment of Pb poisoning and diet-induced obesity. METHODS AND RESULTS: Male Kunming mice were fed a high-fat/high-sugar (HFHS) diet for 6 weeks, then received Pb exposure and Lactiplantibacillus plantarum P101 supplementation for 2 weeks. The histopathology of the liver and colon was observed, and biochemical indicators and gene expression levels were measured. CONCLUSIONS: Here, we reported that Pb exposure exacerbated the existing oxidative stress and gut barrier injury in obese mice, leading to more severe Pb accumulation, and hepatic inflammatory injury compared with normal diet-fed mice. It is worth noting that the P101 treatment significantly reduced Pb accumulation by promoting fecal Pb excretion and enhanced the antioxidant capacity of mice. After P101 treatment, obesity-related indicators were downregulated, and the hepatic injury and gut barrier disruption in mice were alleviated effectively.

5-Aminosalicylic acid ameliorates dextran sulfate sodium-induced colitis in mice by modulating gut microbiota and bile acid metabolism.

Colitis develops via the convergence of environmental, microbial, immunological, and genetic factors. The medicine 5-aminosalicylic acid (5-ASA) is widely used in clinical practice for colitis (especially ulcerative colitis) treatment. However, the significance of gut microbiota in the protective effect of 5-ASA on colitis has not been explored. Using a dextran sulfate sodium (DSS)-induced colitis mouse model, we found that 5-ASA ameliorated colitis symptoms in DSS-treated mice, accompanied by increased body weight gain and colon length, and a decrease in disease activity index (DAI) score and spleen index. Also, 5-ASA alleviated DSS-induced damage to colonic tissues, as indicated by suppressed inflammation and decreased tight junction, mucin, and water-sodium transport protein levels. Moreover, the 16S rDNA gene sequencing results illustrated that 5-ASA reshaped the disordered gut microbiota community structure in DSS-treated mice by promoting the abundance of Bifidobacterium, Lachnoclostridium, and Anaerotruncus, and reducing the content of Alloprevotella and Desulfovibrio. Furthermore, 5-ASA improved the abnormal metabolism of bile acids (BAs) by regulating the Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5) signaling pathways in DSS-treated mice. In contrast, 5-ASA did not prevent the occurrence of colitis in mice with gut microbiota depletion, confirming the essential role of gut microbiota in colitis treatment by 5-ASA. In conclusion, 5-ASA can ameliorate DSS-induced colitis in mice by modulating gut microbiota and bile acid metabolism. These findings documented the new therapeutic mechanisms of 5-ASA in clinical colitis treatment.

New insights into the bile acid-based regulatory mechanisms and therapeutic perspectives in alcohol-related liver disease.

Cholestasis is a key causative factor in alcohol-related liver disease (ALD) and variable degrees of cholestasis occur in all stages of ALD. However, the pathogenetic mechanisms and biomarkers associated with cholestasis are not well characterized. Cholestatic disease is marked by the disruption of bile acids (BA) transport and homeostasis. Consequently, in both human and experimental ALD, the disease shows a direct correlation with an imbalance in BA equilibrium, which in turn may also affect the severity of the disease. Modulation of BA metabolism or signaling pathways is increasingly considered as a potential therapeutic strategy for ALD in humans. In this paper, we highlight the key advances made in the past two decades in characterizing the molecular regulatory mechanisms of BA synthesis, enterohepatic circulation, and BA homeostasis. We summarize recent insights into the nature of the linkage between BA dysregulation and ALD, including the abnormal expression of genes involved in BA metabolism, abnormal changes in receptors that regulate BA metabolism, and disturbance in the gut flora engaged in BA metabolism caused by alcohol consumption. Additionally, we provide novel perspectives on the changes in BAs in various stages of ALD. Finally, we propose potential pharmacological therapies for ALD targeting BA metabolism and signaling.

Saikosaponins regulate bile acid excretion in mice liver and ileum by activating farnesoid X receptor and bile acid transporter.

Radix Bupleuri exerts effective hepatoprotective and cholagogic effects through its Saikosaponins (SSs) component. Therefore, we attempted to determine the mechanism of saikosaponins used to promote bile excretion by studying their effects on intrahepatic bile flow, focusing on the synthesis, transport, excretion, and metabolism of bile acids. C57BL/6N mice were continuously gavaged with saikosaponin a (SSa), saikosaponin b2 (SSb2 ), or saikosaponin D (SSd) (200 mg/kg) for 14 days. Liver and serum biochemical indices were determined using Enzyme-linked immunosorbent assay (ELISA) kits. In addition, an ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) was used to measure the levels of the 16 bile acids in the liver, gallbladder, and cecal contents. Furthermore, SSs pharmacokinetics and docking between SSs and farnesoid X receptor (FXR)-related proteins were analyzed to investigate the underlying molecular mechanisms. Administration of SSs and Radix Bupleuri alcohol extract (ESS) did not cause significant changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels. Saikosaponin-regulated changes in bile acid (BA) levels in the liver, gallbladder, and cecum were closely related to genes involved in BA synthesis, transport, and excretion in the liver. Pharmacokinetic studies indicated that SSs were characterized by rapid elimination (t1/2 as 0.68-2.47 h), absorption (Tmax as 0.47-0.78 h), and double peaks in the drug-time curves of SSa and SSb2 . A molecular docking study revealed that SSa, SSb2 , and SSd docked well with the 16 protein FXR molecules and target genes (<-5.2 kcal/mol). Collectively, saikosaponins may maintain BA homeostasis in mice by regulating FXR-related genes and transporters in the liver and intestine.

The Potential of Bile Acids as Biomarkers for Metabolic Disorders.

Bile acids (BAs) are well known to facilitate the absorption of dietary fat and fat-soluble molecules. These unique steroids also function by binding to the ubiquitous cell membranes and nuclear receptors. As chemical signals in gut-liver axis, the presence of metabolic disorders such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), and even tumors have been reported to be closely related to abnormal levels of BAs in the blood and fecal metabolites of patients. Thus, the gut microbiota interacting with BAs and altering BA metabolism are critical in the pathogenesis of numerous chronic diseases. This review intends to summarize the mechanistic links between metabolic disorders and BAs in gut-liver axis, and such stage-specific BA perturbation patterns may provide clues for developing new auxiliary diagnostic means.

The Black Box Orchestra of Gut Bacteria and Bile Acids: Who Is the Conductor?

Over the past decades the potential role of the gut microbiome and bile acids in type 2 diabetes mellitus (T2DM) has been revealed, with a special reference to low bacterial alpha diversity. Certain bile acid effects on gut bacteria concern cytotoxicity, or in the case of the microbiome, bacteriotoxicity. Reciprocally, the gut microbiome plays a key role in regulating the bile acid pool by influencing the conversion and (de)conjugation of primary bile acids into secondary bile acids. Three main groups of bacterial enzymes responsible for the conversion of bile acids are bile salt hydrolases (BSHs), hydroxysteroid dehydrogenases (HSDHs) and enzymes encoded in the bile acid inducible (Bai) operon genes. Interventions such as probiotics, antibiotics and fecal microbiome transplantation can impact bile acids levels. Further evidence of the reciprocal interaction between gut microbiota and bile acids comes from a multitude of nutritional interventions including macronutrients, fibers, prebiotics, specific individual products or diets. Finally, anatomical changes after bariatric surgery are important because of their metabolic effects. The heterogeneity of studies, diseases, bacterial species and (epi)genetic influences such as nutrition may challenge establishing specific and detailed interventions that aim to tackle the gut microbiome and bile acids.

Chronic Heat Stress Affects Bile Acid Profile and Gut Microbiota in Broilers.

Heat stress (HS) can inhibit the growth performance of broilers and cause substantial economic losses. Alterations in bile acid (BA) pools have been reported to be correlated with chronic HS, yet the specific mechanism and whether it is related to gut microbiota remains unclear. In this study, 40 Rugao Yellow chickens were randomly selected and distributed into two groups (20 broilers in each group) when reaching 56-day age: a chronic heat stress group (HS, 36 ± 1 °C for 8 h per day in the first 7 days and 36 ± 1 °C for 24 h in the last 7 days) and a control group (CN, 24 ± 1 °C for 24 h within 14 days). Compared with the CN group, total BAs' serum content decreased, while cholic acid (CA), chenodeoxycholic acid (CDCA), and taurolithocholic acid (TLCA) increased significantly in HS broilers. Moreover, 12α-hydroxylase (CYP8B1) and bile salt export protein (BSEP) were upregulated in the liver, and the expression of fibroblast growth factor 19 (FGF19) decreased in the ileum of HS broilers. There were also significant changes in gut microbial composition, and the enrichment of Peptoniphilus was positively correlated with the increased serum level of TLCA. These results indicate that chronic HS disrupts the homeostasis of BA metabolism in broilers, which is associated with alterations in gut microbiota.